Diabetes mellitus is a metabolic disorder in which the ability to utilize glucose is partly or completely lost (designated diabetes 2 and diabetes 1, respectively). World vide, about 5% of all people suffer from diabetes and the disorder approaches epidemic proportions. Since the introduction of insulin in the early 1920's, continuous efforts have been made to improve the treatment of diabetes mellitus. Since many people suffering from diabetes are subject to chronic treatment over several decades, there is a major need for safe, convenient and life quality improving insulin formulations.
In the treatment of diabetes mellitus, many varieties of insulin formulations have been suggested and used, such as regular insulin, isophane insulin (designated NPH), insulin zinc suspensions (such as Semilente®, Lente®, and Ultralente®) and biphasic isophane insulin. Some of the commercial available insulin formulations are characterized by a fast onset of action and other formulations have a relatively slow onset but show a more or less prolonged action. Fast-acting insulin formulations are usually solutions of insulin, while retarded acting insulin formulations can be suspensions containing insulin in crystalline and/or amorphous form precipitated by addition of zinc salts alone or by addition of protamine or by a combination of both. Recently, also soluble prolonged acting insulin formulations have also been put on the market and in such formulations the insulin may be an acylated insulin.
Some previously invented insulins and insulin analogues which are acylated with a fatty acid chain with high affinity for albumin have—due to analogue design—high hydrophobicity or changed pI value (compared with that of human insulin). Subcutaneous injection of such an acylated insulin may result in precipitation by salting out or oligomer formation of the acylated insulin. Unfortunately, the precipitated, acylated insulin is only partly solubilised in the subcutis. One draw back of this is that these insulins when injected have limited bioavailability and, hence, it is difficult to control the administration of insulin.
It has turned out that it is extremely important for a diabetic patient to control the blood glucose level as much as possible. A good control of the blood glucose level will—in addition to the control of the diabetic disease—reduce the risk for complications such as cardiovascular diseases, amputation of legs and blindness.
In J. Histochem. Cytochem. 36 (1988), 359-65, receptor dynamics of gold-insulin complexes, stabilized with bovine serum albumin, was studied. No pharmaceutical formulations are mentioned therein.
The claims in U.S. Pat. No. 2,789,080 relates to an aqueous composition comprising insulin and an esterified animal albumin. Alternatively, the albumin can be amidificated. Since this patent claims priority from 1953, the insulin dealt with probably is porcine or bovine insulin.
Claim 1 in U.S. Pat. No. 4,492,684 relates to a composition comprising a matrix of partially cross-linked albumin and insulin, said cross-linking being achieved by the use of glutaraldehyde resulting in covalent bonds.
Claim 1 in U.S. Pat. No. 4,963,526 relates to a composition useful as an oral dosage form of insulin, said composition derived from a two phase liquid coacervate composition. According to claim 3 therein, said composition may, for example, contain albumin. Apparently, no acylated insulin is mentioned therein.
Claim 1 in U.S. Pat. No. 6,051,551 relates to a method of treating diabetes, comprising administering a fatty acid-acylated human insulin or insulin analogue by inhalation. According to columns 11 and 12 therein, formulations suitable for use with a sprayer or a nebulizer can also include an agent for stabilizing of the fatty acid-acylated insulin protein, such as, for example, a bulk protein. Bulk proteins include, for example, albumin. Albumin is not used in any of the working examples therein.
Claim 1 in WO 92/19260 relates to a peptide hormone solution said solution containing serum albumin in an amount capable of stabilizing the hormone to prevent precipitation thereof. In the only experimental example in said application, the hormone insulin, of an unknown species, is used.
Claim 20 in WO 02/064115 relates to a powder insulin formulation manufactured by lyophilization of a dispersion of a liquid insulin formulation according to claim 1 therein to which has been added a cryoprotectant which, for example, is albumin. No acylated insulins are mentioned therein.
Claim 1 in WO 2008/013938 relates to an aerosolizable formulation comprising an insulin derivative. At page 34 therein, albumin is mentioned as one of the many, possible ingredients in the aerosolizable formulation.
Claim 1 in WO 2008/034881 relates to novel, protease resistant insulin analogues which have been developed for oral administration for patients preferring that route of administration. The preparation of oral formulations is described therein at pages 31-34 and, at page 34, albumin is mentioned as one of the many, possible ingredients in the oral formulation.